A Nature-Inspired Design Yields a New Class of Steroids Against Trypanosomatids

Aguilera, Elena; Perdomo, Carlos; Espindola, Alejandra; Corvo, Ileana; Faral-Tello, Paula; Robello, Carlos; Serna, Elva; Ferreira, Francisco; Riveros, Rocío; Torres, Susana; Bilbao, Ninfa I Vera de; Yaluff, Gloria; Álvarez, Guzmán

doi:10.3390/molecules24203800

Cited by 12 publications

(20 citation statements)

References 36 publications

(57 reference statements)

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“…Finally, the acute toxicity in mice of compound 796 was evaluated by the up and down test, resulting in an LD50 > 2000 mg/kg of weight. Hit compounds 266 and 314 were previously evaluated in our group with this test, obtaining the same result [ 13 , 16 ].…”

Section: Resultsmentioning

confidence: 91%

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Preclinical Studies in Anti-Trypanosomatidae Drug Development

et al. 2021

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The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

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Section: Resultsmentioning

confidence: 91%

“…In previous works by our group, this test had already been carried out on compounds 266 and 314 , finding that they are not genotoxic. They also have a negative AMES test that evaluates the mutagenic capacity of the molecules [ 13 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

Preclinical Studies in Anti-Trypanosomatidae Drug Development

et al. 2021

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“…For the anti- Trypanosoma and anti- Leishmania activity assays, we followed the methods described by Aguilera et al, 2019 [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…The cytotoxicity of the dewaxed dichloromethane extract of U. hecatantha and the isolated compounds was evaluated according to the method described by Aguilera et al, 2019 [ 15 ]. The J774.1 murine macrophages (ATCC, USA) were grown in a DMEM culture medium containing 4 mM L-glutamine and supplemented with 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

Antiprotozoal Compounds from Urolepis hecatantha (Asteraceae)

Elso

Clavin

Hernández

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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The dewaxed dichloromethane extract of Urolepis hecatantha and the compounds isolated from it were tested for their in vitro activity on Trypanosoma cruzi epimastigotes and Leishmania infantum promastigotes. The extract of U. hecatantha showed activity against both parasites with IC50 values of 7 µg/mL and 31 µg/mL, respectively. Fractionation of the dichloromethane extract led to the isolation of euparin, jaceidin, santhemoidin C, and eucannabinolide. The sesquiterpene lactones eucannabinolide and santhemoidin C were active on T. cruzi with IC50 values of 10 ± 2 µM (4.2 µg/mL) and 18 ± 3 µM (7.6 µg/mL), respectively. Euparin and santhemoidin C were the most active on L. infantum with IC50 values of 18 ± 4 µM (3.9 µg/mL) and 19 ± 4 µM (8.0 µg/mL), respectively. Eucannabinolide has also shown drug-like pharmacokinetic and toxicity properties.

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“…Moreover, the presence and inherent reactivity of their α,β-unsaturated ketone system can also be associated with potential toxicity problems, including mutagenesis and carcinogenesis [ 31 , 32 ]. Despite this, over the years, various arylidenesteroids have been studied, namely as hydroxysteroid dehydrogenases, aromatase, and 5α-reductases inhibitors, as well as skeletal muscle relaxants, antimicrobial, neuroprotective, antiparasitic, and antiproliferative agents [ 17 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Additionally, other research works have been demonstrating their use as synthetic intermediates, mainly in the preparation of aza-heterocycles with relevant potential applications [ 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

et al. 2021

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Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17β-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds.

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A Nature-Inspired Design Yields a New Class of Steroids Against Trypanosomatids

Cited by 12 publications

References 36 publications

Preclinical Studies in Anti-Trypanosomatidae Drug Development

Preclinical Studies in Anti-Trypanosomatidae Drug Development

Antiprotozoal Compounds from Urolepis hecatantha (Asteraceae)

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

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